PROJECT 2 SUMMARY The main focus of the current proposal is the identification of genetic factors influencing episodic memory function in cognitively healthy elderly by examining a specific set of genes associated with changes in the aging hippocampus. The identification of molecular pathways underlying memory function in cognitively healthy individuals is expected to pinpoint mechanisms for preventing or delaying cognitive decline that might be distinct from those identified by studies of subjects with cognitive impairment or dementia. In a recent study aiming to isolate molecular correlates of the aging human dentate gyrus (DG) and age- related memory loss, investigators of this P50 application identified substantial age-related changes in the human DG expression of 17 genes. Increasing abundance of the gene showing the strongest association (RbAp48) in the DG of aged mice was accompanied by improved memory performance (Pavlopoulos et al. Sci Transl Med. 2013 Aug 28;5(200):200ra115). RbAp48 plays multiples roles in histone acetylation, transcriptional regulation and the cyclic adenosine monophosphate (cAMP) protein kinase A (PKA) cAMP response element binding protein 1 (CREB1) pathway required for normal hippocampal function and aging. In initial analyses we tested whether genetic variants in RbAp48, CREB1 and CREBBP were associated with episodic memory function in large samples of cognitively healthy elderly. Consistent with the idea that this histone pathway is implicated in memory function, we found that cognitively healthy elderly carrying specific variants in these genes showed significantly better average episodic memory function when compared to non-carriers. The overarching aim of this project is to further elucidate the genetic basis of episodic memory function in cognitively healthy individuals by exploring the association of variants in the full list of 17 genes showing age- related expression changes in the DG with episodic memory function, three genes acting in the CREB1 pathway and additional variants in genes outside these pathways in several independent cohorts of cognitively healthy individuals, and to identify the specific genetic variants by targeted resequencing. We aim to follow-up and validate identified mutations by genotyping in several independent cohorts as well as bioinformatics and biophysical analyses assessing the effect of identified mutations on protein structure, level and function.